1. Field of the Invention
The present invention relates to a process for the production of one of the group of 3-allyl- and 3-butenyl-3-cephems and 3-carbocyclic- and -heterocyclic methyl-3-cephem derivatives by providing a 3-chloroethyl-3-cephem intermediate, reacting the intermediate with an appropriate hydrocarbyl tributylstannane in the presence of bis(dibenzylideneacetonyl)-palladium and a phosphine and a metal halide. The resulting 3-allyl- and butenyl- and -carbocyclic methyl- and -heterocyclic methyl-3-cephems are useful as broad spectrum antibacterial agents.
2. Background Art
Hoshi et al., U.S. Pat. Nos. 4,591,641 (5/86) and 4,520,022 (5/85), both of which are owned by the assignee of the present invention, disclose vinyl-substituted cephalosporins having the 3-((Z)-1-propenyl) and 7-phenylglycylamido groups represented by the structural formula, A, ##STR1## wherein the 3-propenyl group has the (Z)-configuration. These patented compounds were produced by forming a substituted vinyl group in the 3-position of the cephalosporin nucleus by reacting a 3-halomethyl cephalosporin or an alkyl halide (e.g., methyl halide) with a triarylphosphine to yield a phosphoranyl intermediate which is then treated with a alkylhydrogencarbonyl reagent or a 3-hydrogencarbonyl cephalosporin, respectively. The foregoing compounds were produced by application of the synthetic routes disclosed in U.S. Pat. Nos. 3,769,277 (10/73), 3,994,884 (11/76), and 4,107,431 (8/78).
Long et al., U.S. Pat. No. 3,769,277 (10/73) disclose .DELTA..sup.3 -4-carboxy cephalosporins of the formula ##STR2## by reacting a 3-formyl (i.e. a 3-hydrogencarbonyl)cephalosporin with a phosphorane of the formula R.sub.3 P.dbd.CR.sup.3 R.sup.4.
Weir, U.S Pat. No. 3,994,884 (11/76) discloses the preparation of .DELTA..sup.3 -4-carboxy cephalosporin having a 3-vinyl group by reacting the corresponding 3-halomethyl cephalosporin compound with a phosphine to obtain the phosphonium intermediate, converting the phosphonium intermediate to the corresponding phosphoranylidene intermediate, and coupling the phosphoranylidene intermediate with formaldehyde.
Clark, et al., U.S. Pat. No. 4,107,431 (8/78) (GB1342241), disclose the preparation of .DELTA..sup.3 -vinyl or substituted vinyl-4-carboxy cephalosporins by reacting a 3-phosphoranylidene cephalosporin with a carbonyl compound of the formula R.sup.3 COR.sup.4 or by reacting a 3-formyl cephalosporin with a phosphorane of the formula R.sub.3 P.dbd.CR.sup.3 R.sup.4.
O'Callaghan et al., U.S. Pat. No. 3,830,700 (8/74), disclose certain 3-arylvinvyl cephalosporins useful as chromogenic agents for the detection of .beta.-lactamase activity. The compounds useful in the patented method were prepared by reacting a 3-phosphoranylidene cephalosporin with a hydrogencarbonyl aryl (aryl aldehyde) compound or by reacting a 3-hydrogencarbonyl cephalosporin with a phosporane of the formula (R).sub.3 P.dbd.CHAr.
Beeby, U.S. Pat. Nos. 3,983,113 (9/76), 4,049,806 (9/77), and 4,139,618 (2/79) disclose 3-(heterocyclothio)propenyl cephalosporins represented by the formula ##STR3## wherein the compounds were prepared by reacting the starting 3-formyl cephalosporin with a suitable vinyl Grignard reagent to obtain a mixture of .alpha.- and .beta.-hydroxy isomers of the corresponding 3-(1-hydroxyprop-2-enyl) cephalosporin followed by treating the foregoing intermediate with a mercapto substituted heterocycle corresponding to the SR.sup.1 substituent in the presence of a small amount of strong acid. Beeby, U.S. Pat. No. 4,112,087 (9/78) discloses compound having the formula shown above except that "OR" is substituted for "S--R.sup.1 ".
Webber, U.S Pat. No. 4,065,620 (12/77) discloses 3-(substituted) vinyl cephalosporins prepared by reacting a 3-formyl cephalosporin compound with a phosphorane of the formula R.sub.1 R.sub.2 R.sub.3 P.dbd.CH--Y under conventional Wittig reaction conditions.
Takaya et al., EP App. Publn. No. 0,030,630 (6/81) disclose 7-acylamino-3-vinylcephalosporanic acid derivatives prepared by reacting a 3-formyl cephalosporin compound with a suitable phosphorane
Miyadera et al., U.S. Pat. No. 4,147,863 (4/79) disclose cephalosporin derivatives having a (1-alkyl-1H-tetrazol-5-yl)vinyl group at the 3-position of the cephem nucleus. The patent discloses preparation of the intermediate having the given 3-vinyl substituent by reacting a known 3-formyl cephalosporin with a Wittig reagent (phosphorane).
Beattie et al., U.S. Pat. No. 4,255,423 (3/81) disclose cephalosporin compounds having a substituted or unsubstituted vinyl group at the 3-position of the cephalosporin nucleus prepared by the reaction of a phosphoranylidene compound with a compound containing a carbonyl group. More particularly, a phosphoranylidene compound of the formula ##STR4## may be reacted with a carbonyl compound of the formula R.sub.2 --CO--R.sub.3 to obtain the --CH.dbd.CR.sub.2 R.sub.3 substituent at the 3-position of the cephem nucelus.
It is known in the art to which this invention and the compounds thereby produced relate that it is possible to chemically modify naturally occurring cephalosporins by performing chemical reactions at the C(3)-position and C(3)-position side chain of the 3-cephem nucleus in an effort to discover novel antibiotics. See "Chemistry and Biology of .beta.-Lactam Antibiotics. Volume 1. Penicillins and Cephalosporins," R. B. Morin and M. Gorman, Ed., Academic Press, New York, 1982.
Notaby absent in the field of cephalosporin chemistry is a general method for producing 3-cephem derivatives by means of carbon-carbon bond formation at the C(3')-position of the 3-cephem nucleus.
Heck, R. F. in "Palladium Reagents In organic Synthesis," Academic Press, Orlando, FL, 1985, discloses the use of various Pd reagents in various synthetic operations.
Scott, Crisp and Stille, J. Amer. Chem. Soc., 106, 4630(1984) described the palladium-catalyzed coupling of organotins with electrophiles facilitated by the addition of zinc chloride.
Scott and Stille, J. Amer. Chem. Soc., 108, 3033(1986) described the palladium-catalyzed coupling reaction of several vinyl triflates with organostannanes such as, for example, vinyltributylstannane to yield a product having the vinyl group bonded to the carbon atom which has been vacated by the triflate group.
In connection with work on the development of new broad spectrum semisynthetic cephem antibiotics, we conceived that natural cephalosporins, bearing a potential leaving group at an allylic position, should in principle be amenable to palladium (0)-promoted displacement. Our initial attempts to couple the compound having formula E with vinyltributyl stannance in the presence of Pd catalysts were, however, unsuccessful. ##STR5##
We found that the readily available chloromethylcephems (e.g., Otsuka Co.) reacted, albeit extremely slowly, with organostannanes in reluxing THF in the presence of Pd(OAc).sub.2 under conditions reported by F. K. Sheffy, J. P. Goldshalx, and J. K. Stille, J. Amer. Chem. Soc., 106, 4833 (1984). The use of more polar or higher-boiling solvents produced extensive decomposition.
However, using a catalytic system prepared by adding tri-(2-furyl)-phosphine to a THF solution of bis(dibenzylideneacetonyl)palladium(0), the reaction proceeded at a convenient rate, and coupling with a variety of stannanes (Eq. 1) took place in good yield. ##STR6##